Patent HU-9902606-A2 (HU)
Title: Matrix metalloproteinase inhibitors
Inventor: ABRATE FRANCESCA
IPC: A61K31/16
Filed: 1997-06-20
Abstract: Succinic amide derivatives of formula WCH(NRR1)CH(R2)CONHCH(R3)COR4 (I) and their salts, prodrugs, solvates and hydrates are new. W = CO2H or CONHOH; R = H, 1-6C alkyl, Ph or benzyl; R1 = H; or lower alkyl (especially Me, Et, Pr, i-Pr, i-Bu, t-Bu), aryl (especially Ph or naphthyl), or aryl (lower alkyl) (especially benzyl), all optionally substituted by one or more of Me, Et, i-Pr, t-Bu, F, Cl, Br, NO2, NH2, NMe2, OH, MeO, EtO, acetyl, acetamido, carboxy or carboxymethyl; (CH2)m heterocyclyl; (CH2)m cyclopropyl; (CH2)nCO2H; (CH2)mCOOR1'; (CH2)mSO2R1'; (CH2)mSO2NH2; (CH2)mSO2NMe2; (CH2)mSO2NHR1'; (CH2)mSO2-(4-morpholino); (CH2)mSO2(1-piperazino); (CH2)mSO2(4-methyl-1-piperazino); (CH2)nSO3H; acyl (especially acetyl, benzoyl or phenacetyl) optionally substituted by one or more of Br, Cl, F, MeO, EtO, Me, Et, benzyl, Ph, OH, O, carboxy or NO2; C(O)R11C(O)R111; C(O) heterocyclyl; C(O)R11-heterocyclyl; C(O)R11-aryl; or NRR1 = morpholino, pyrrolidino, piperazino, N-methyl-piperazino, succinimido or phthalimido; m = 0-3; heterocyclyl = 3-6 membered heterocycle, simple or condensed with a benzene or naphthalene ring, containing at least one N (preferably succinimido, phthalimido, saccharin, hydantoin, indolyl, oxyindolyl, 2-oxo-isoindolinyl, imidazolyl, pyridyl, morpholino, pyrrolidino, 2-oxo-pyrrolidino or piperazino), and optionally substituted by one or more of Br, Cl, F, MeO, EtO, Me, Et, benzyl, Ph, OH, O, carboxy or NO2; n = 1-3; R1' = Me, Et, Pr, i-Pr, i-Bu, t-Bu, Ph, benzyl, allyl, styryl, 1-naphthyl, 2-naphthyl, all substituted by 0-3 of Me, Et, i-Pr, t-Bu, F, Cl, Br, NO2, NH2, NMe2, OH, MeO, EtO, acetyl, acetamido, carboxy or carboxymethyl; R11 = bond, CH2, CH2(CH2)mCH2, CH=CH, CH2CH=CH, phenylene, CH2CH=CHC6H4, CH2CH2CH=CH, CH2CC, CH2CH2CC, CH2CH2CH=CHC6H4, CH2CCC6H4 or CH2CH2CCC6H4; R111 = Me, Et, Ph, OH, MeO, EtO, NH2, NMe2, NHMe or morpholino; R2 = 3-15C alkyl optionally substituted by 3-7C cycloalkyl; R11H where R11 is substituted by 0-3 of Me, Et, 3-4C alkyl, F, Cl, 1-4C alkoxy, NO2, NH2, NMe2, carboxy or carboxymethyl; or R11 X R1v; R1v = 1-6C alkyl, 3-7C cycloalkyl, 2-6C alkenyl, Ph, Ph (1-6C alkyl) or Ph (2-6C alkenyl), optionally substituted by F, Cl, Br, 1-4C alkyl or 1-4C alkoxy; X = bond, O, S, SO, SO2, CONH or NHCO; R3 = characterising group of a natural or non-natural ~a-aminoacid with any functional groups optionally protected; R4 = O-(1-4C alkyl) or O-phenyl and derivatives thereof substituted by 0-3 of 1-4C alkyl, Cl or MeO; NH2; NH (1-6C alkyl); NH-aryl; NH-heterocyclyl; NH (1-6C alkyl) substituted by Ph or heterocyclyl; NH (2-6C alkyl) substituted by CONH2, NHCONH2, SO2NH2, NHSO2NH2 or derivatives thereof where the terminal N is substituted by one or two Me, or is part of a morpholino, pyrrolidino, piperazino, or N-methylpiperazino; NH (2-6C alkyl) substituted by optionally protected amino, mono (1-6C alkyl)amino, di (1-6C alkyl)amino, guanidino, morpholino, piperazino or N-methylpiperazino; R3 + R4 = (CH2)m'NH optionally interrupted by NR5, by C6H4O or by an indole ring linked through its C3 and N atoms; m' = 5-12; R5 = H, 1-6C alkyl, 1-6C alkoxycarbonyl, aryl, aryl (1-6C alkyl), or aryl (1-6C alkoxy)carbonyl; and all alkyl, alkenyl, Ph, cycloalkyl, heterocyclyl and characterising groups are optionally substituted; provided that when NRR1 = NH2 protected amino or acylamino, R3 = t-Bu and R4 = amino or alkylamino, then R2 is not isobutyl.